Addressing Treatment-Resistant Depression: Opportunities and Challenges

CLINICAL REFLECTIONS

According to a recent US study, 30.9% of those treated for major depressive disorder (MDD) show treatment resistant depression (TRD) in 12 months.¹ However, international estimates of TRD prevalence range from 6% to 55% of patients receiving antidepressant treatment.² This wide range of estimates has been attributed to ambiguities in TRD definitions across translational research and treatment development—ambiguities that persist through clinical and policy decision-making.² The lack of consensus on a definition has been suggested to negatively impact comparative treatment research and understanding of biological mechanisms, resulting in inconsistent medical insurance coverage.³

Advanced practice providers (APPs) such as physician assistants (PAs) and nurse practitioners (NPs) play a critical role in the diagnosis and treatment of psychiatric disorders, improving access to health care services.⁴ PAs and NPs serve as key members of a health care team, taking on responsibilities and duties across the clinical spectrum to expand access to patients who seek treatment for depression.

Considerations for a TRD Diagnosis

Despite recognition that TRD must be addressed, there is no precise definition. The US Centers for Medicare & Medicaid Services (CMS) convened a public meeting of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) in 2016 to obtain independent recommendations and expert advice regarding the definition of TRD.⁵ Although the MEDCAC panel supported the establishment of an evidence-based, operational definition of TRD, they did not officially define the condition.³ Similarly, the US Food and Drug Administration (FDA) and the European Medicines Administration (EMA) convened, where they defined TRD as the failure to respond to 2 or more antidepressant agents despite adequate dosage, duration, and treatment adherence.^2,6,7

In addition to honing the definition of TRD, clinicians should rule out pseudo-resistance, which is a possibility when a patient does not respond to treatment but the criteria for TRD have not been met.⁸ Misdiagnosis of MDD, a lack of adequate medication trials, and individual differences in the metabolism of antidepressants contribute to pseudo-resistance.²

Inaccurate assessment of treatment response due to the lack of measurable, quantifiable, and agreed-upon endpoints can also inhibit an accurate diagnosis.² This is especially significant in the primary care setting, where initial treatment of MDD often occurs.² Measurement-based care and the systematic use of standardized measurements to inform treatment decisions is often not implemented in these settings, meaning clinicians are not leveraging the widely accepted, validated, self-report questionnaires (eg, 9-item Patient Health Questionnaire and the 21-item Beck Depression Inventory) that support clinical care by measuring symptoms.⁹

Further complicating the clinical picture, measuring the core feature of anhedonia (ie, loss of desire, effort, and the inability to experience pleasure or enjoyment from activities that were previously pleasurable) is complex and varies between scales.^10,11 Meanwhile, almost 70% of patients with depression experience anhedonia, and the effectiveness of traditional antidepressants in addressing it is limited.¹¹

Ultimately, the lack of a consensus definition of TRD and subsequent discrepancies in practice behavior contribute to suboptimal treatment interventions and compromised health outcomes for patients.² Wider adoption of standardized measurements and the assessment of treatment responses would aid health care professionals (HCPs) in the diagnosis and treatment of TRD.

Evolving Roles for TRD Treatment

Although the precise roles for APPs vary depending on the practice and the individual patient visit, they are increasingly taking on the diagnosis and management of psychiatric disorders, with physicians sometimes seeing the patient or just providing advice.¹²

In October 2024, 27 states and the District of Columbia approved NP full practice authority, which is defined by the American Association of Nurse Practitioners as “the collection of state practice and licensure laws that allow for nurse practitioners to evaluate patients, diagnose, order and interpret diagnostic tests, initiate and manage treatments—including prescribe medications—under the exclusive licensure authority of the state board of nursing” (Figure 1).^13,14 This allows NPs to practice to the fullest extent of their education and training. Some states may require experience or additional training before allowing full practice authority.

Although PAs have supervisory or collaborative agreements in most states, several have removed supervision requirements, granting PAs wider autonomy.¹⁵ In fact, a recent survey found that 3 out of 4 PAs practice independently, with state-mandated supervision or collaboration often functioning as a clerical formality.¹⁶

Despite these statistics, there is reason to believe PAs and NPs are not being fully utilized. For instance, data from an ambulatory care study found that PAs and NPs were involved in only 6.7% of depression visits and were the sole provider in 2.9% of the cases.⁴ A more recent analysis found stronger results: the proportion of health care visits delivered by either a PA or an NP increased from 14% in 2013 to 25.6% in 2019.¹² The data is more positive in psychiatry, where visits delivered by PAs and NPs for mood disorders, anxiety disorders, andschizophrenia diagnoses were 33.8%, 36.7%, and 37.9%, respectively.¹² 

Data similarly shows underutilization in inpatient care. A recent study of 9 inpatient psychiatric facilities across 3 states found that several had not even considered PAs for inpatient care.

Shared Decision-Making and the Need for Compassionate Care

Treatment options for TRD should be discussed openly with patients to facilitate shared decision-making (SDM).¹⁷ This collaborative process encourages both the patient and provider to exchange information, align on preferred treatment options, and mutually agree on a care plan. Discussions should cover symptom management, potential adverse effects, and strategies for managing adverse effects. ¹⁸ 

The Agency for Healthcare Research and Quality (AHRQ) developed the SHARE approach (Figure 2), which outlines 5 key steps to guide SDM.^19,20 These steps are summarized as:

• Seek the patient’s participation
• Help the patient to understand treatment options
• Assess the patient’s values and preferences
• Reach a decision
• Evaluate the patient’s decision

Studies suggest that SDM increases patient engagement and improves treatment adherence, all of which are essential for TRD.²¹

Although worthwhile, this approach is time-intensive and busy practices and clinics may have limited time to devote to appropriate SDM. By expanding the health care team with PAs and NPs, we make more room for thoughtful and patient-centered treatment decisions, ultimately improving adherence and outcomes.

In addition, NPs and PAs can take some of the load of patient education, answering questions about their treatment, risks, adverse effects, costs, and duration in a supportive environment.²²

Moving Beyond Stigma to Effective Treatment

The term treatment-resistant depression can be stigmatizing and may discourage patients from feeling optimistic about their prognosis. Instead, it should be framed that the medication is not eliciting an adequate response, and there is an opportunity to explore different approaches.

The goal of treatment should be complete remission, not just symptom reduction, as full remission is linked to better long-term outcomes.^23,24 Five specific patient-centered measures have been associated with remission from depressive symptoms at 6 months, namely inquiring about patient preferences for care, discussing any questions or concerns, providing treatment plans, utilizing depression scales, and asking about suicide risk.¹⁷

PAs and NPs can also play a key role in implementing novel, faster-acting treatments for TRD. Therapeutic options beyond monoamine modulation have demonstrated rapid symptom relief and improved treatment response rates, and prioritizing aggressive initial treatment and maintaining an appropriate dosage is key in managing TRD.^23-25 Novel interventions that target central neurotransmitters, such as opioid receptor modulators, cholinergic compounds, and γ-aminobutyric acid modulators, and non-competitive N-methyl D-aspartame receptor agonists, such as ketamine and esketamine, have been shown to exhibit antidepressant effects within hours of intravenous infusion or intranasal administration, respectively.

APPs should be prepared to educate patients about these interventions and help shift the treatment mindset toward a more urgent approach when appropriate. Education is required to change the mindset around the urgency of treatment, as this may have a large impact on the patient’s everyday life.

Concluding Thoughts

In the treatment landscape for depression, there is a need for a clear and consistent application of the definition of TRD to address inconsistencies and issues with treatment protocol and approval. With their expanding and ever-evolving roles, PAs and NPs are ideally positioned to engage patients with TRD and have a meaningful impact on their quality of life.

Although managing the treatment for such patients can be challenging, it is firmly within the scope of the APP to manage difficult cases, and PAs and NPs should be encouraged to further specialize and develop autonomy within their health care team.

Acknowledgments

Medical writing and editorial assistance were provided by Melissa Vetten, PhD, of Medistrava, an Inizio Company, in accordance with Good Publication Practice (GPP 2022) guidelines, funded by Janssen Scientific Affairs, LLC, and under the direction of the authors.

Disclosures

This research was supported by Janssen Scientific Affairs, LLC, a Johnson & Johnson company.

Mr Asbach is on the speaker bureau for AbbVie, Otsuka, Neurocrine, Teva, Axsome, ITCI, and Janssen. He is a consultant for Neurocrine, Teva, ITCI, Karuna, Biogen, and Janssen.

Ms Harris is a consultant for Janssen.

Ms Crown is on the speaker bureau for Axsome Therapeutics, Intracellular Therapies, Janssen Pharmaceuticals, Lundbeck, Neurocrine Biosciences, Otsuka America Pharmaceuticals, Inc., Supernus, and Takeda. She is a consultant for Asxome Therapeutics, Intracellular Therapies, Kanssen Pharmaceuticals, Karuna, Lundbeck, Otsuka America Pharmaceuticals Inc, Supernus, Takeda, and is on faculty (advisory board, honoraria) for Axsome Therapeutics, Intracellular Therapies, Janssen Pharmaceuticals, Otsuka America Pharmaceuticals, Inc. She is a primary investigator for Boehringer Ingelheim.

Ms Clemens is on an advisory board for Janssen and speaker bureau for AbbVie and Biogen/Sage Pharmaceuticals.

Ms Chapman has nothing to disclose regarding the topic.

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